title: Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction.
abstract: Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM) induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. louis.chesler@icr.ac.uk
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.forename: David D
authors.initials: DD
authors.lastname: Goldenberg
authors.forename: Rodney
authors.initials: R
authors.lastname: Collins
authors.forename: Matt
authors.initials: M
authors.lastname: Grimmer
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Kim
authors.initials: K
authors.lastname: Nguyen
authors.forename: Slava
authors.initials: S
authors.lastname: Yakovenko
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation; D002648:Child; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D012074:Remission Induction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D003520:Cyclophosphamide